The central hypothesis of this application is that myocardial aging is dictated by time-dependent changes in the motility of c-kit-positive cardiac stem cells (CSCs). Defective migration of CSCs may oppose their egress from the niches and translocation to the sites of damage in the old heart. A guidance system that regulates stem cell migration involves the family of Eph receptor tyrosine kinases, which interact with the neighboring cells expressing the ephrin ligands. EphA2 receptors are preferentially located on the surface of CSCs, while the corresponding ligand, ephrin A1, is distributed on the membrane of cardiomyocytes, which act as supporting cells within the niches. Activation of EphA2 by ephrin A1 results in directional migration of CSCs, promoting their recruitment to the site of injury, while blockade of the EphA2 pathway abrogates the motile response of CSCs. Abnormalities in ephrin A1/EphA2 signaling may interfere with the translocation of old CSCs in the aging heart. The impaired migration of CSCs in old myocardium may be dictated by: a) reduced synthesis of ephrin A1 by senescent cardiomyocytes; b) decreased expression of EphA2 in CSCs; and/or c) alterations at the translational or post-translational level of EphA2 and its downstream effectors. These possibilities will be tested to identify targets aiming at the recovery of the therapeutic efficacy of old CSCs in the senescent myocardium. Restoration of EphA2 signaling in old CSCs may delay, prevent, or reverse the manifestations of the aging cardiac phenotype. Additionally, we have developed a strategy for the recognition and selective isolation of CSCs with intact regenerative potential from the old heart. With aging, senescent CSCs accumulate in the myocardium; however, a pool of young cells with high growth reserve persists throughout life. These cells are expected to retain ephrin A1/EphA2 signaling capacity and migratory properties. Based on the differential ability of young and old CSCs to activate the ephrin A1 pathway, the pool of functionally-competent CSCs may be harvested and implemented to repopulate the senescent heart with mechanically efficient cardiomyocytes. Ultimately, the profound restructuring of the old heart may prolong the health span and lifespan in humans.